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Future Target for HIV Therapy: T-Cell’s Own Proteins

Future Target for HIV Therapy: T-Cell’s Own Proteins

May 01, 1999

Viruses, such as the human immunodeficiency
virus (HIV), are parasites: to reproduce, they need to appropriate
their hosts resources. Stanford researchers have discovered
that one of HIVs requirements is a cellular protein called NFAT
that allows the virus to multiply in the T- cells of its host. The
T-cell proteins that carry out NFATs instructions, reasoned the
researchers, may make perfect targets for anti-HIV drugs because
these cellular proteinsunlike HIV proteinsare unlikely to
mutate to escape the effects of drugs.

Traditional antiviral therapy works by interfering with protein
targets that are unique to the virus, so that human cells remain
unaffected. This strategy can reduce the severity of side effects,
but it can also allow viruses that mutate rapidly to avoid such drugs
by altering the shape of their proteins.

Each new anti-HIV drug is a step better and, one hopes, less
toxic to the patient, but its still an arms race with the
virus, said Garry Nolan,PhD, assistant professor of molecular
pharmacology. It costs the virus nothing to evolve resistance,
but it costs us many lives and billions of dollars. If you can block
the virus access to something it needs, however, it is a long
evolutionary road for the virus to reestablish access to that resource.

Rest and Unrest

Dr. Nolan and senior postdoctoral fellow Shigemi Kinoshita, PhD,
began their research with the observation that HIV cannot reproduce
in resting T cells. When resting T-cells detect invaders,
they start dividing to fight off the invasion. This activity allows
any HIV hiding passively within those T-cells to make copies of
itself. To find out what part of the T-cell-activation process gives
HIV the opportunity to reproduce, Drs. Kinoshita and Nolan looked at
NFAT, a critical cellular protein needed for normal early activation
of T cells.

Using engineered mouse viruses, Dr. Kinoshita delivered one form of
NFATNFATcto some resting T-cells. Although, NFATc is
crucial to the process of activating resting T-cells, its presence
per se was not sufficient to cause these cells to divide or otherwise
respond as though there were an infection. The cells did, however,
become susceptible to HIV infection.

Possible New Target for Anti-HIV Drugs

This is a subprogram that is not by itself sufficient to
activate the T cell, but activating that subprogram allows HIV to
replicate, said Dr. Nolan. The human immunodeficiency virus can
enter all resting T-cells, but without active NFATc, the virus gets
blocked halfway through the process of converting its RNA into DNA.
Proteins from the virus can only insert the DNA form of viral genetic
material into the human hosts DNA, and only this inserted form
can then produce more virus proteins and genetic material.

Although an HIV enzyme called reverse transcriptase is the primary
protein required for converting RNA into DNA, it gets blocked in the
absence of something provided by the T-cell. That
something may make an excellent target for a whole new
class of HIV-fighting drugs, researchers suggest.

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